1. Field of the Invention
This invention relates to compounds which inhibit cellular xcex2-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer""s disease.
2. References
The following publications, patents and patent applications are cited in this application as superscript numbers:
1 Glenner, et al., xe2x80x9cAlzheimer""s Disease: Initial Report of the Purification and Characterization of a Novel Cerebrovascular Amyloid Proteinxe2x80x9d, Biochem. Biophys. Res. Commun., 120:885-890 (1984).
2 Glenner, et al., xe2x80x9cPolypeptide Marker for Alzheimer""s Disease and its Use for Diagnosisxe2x80x9d, U.S. Pat. No. 4,666,829 issued May 19, 1987.
3 Selkoe, xe2x80x9cThe Molecular Pathology of Alzheimer""s Diseasexe2x80x9d, Neuron, 6:487-498 (1991).
4 Goate, et al., xe2x80x9cSegregation of a Missense Mutation in the Amyloid Precursor Protein Gene with Familial Alzheimer""s Diseasexe2x80x9d, Nature, 349:704-706 (1990).
5 Chartier-Harlan, et al., xe2x80x9cEarly-Onset Alzheimer""s Disease Caused by Mutations at Codon 717 of the xcex2-Amyloid Precursor Protein Genexe2x80x9d, Nature, 353:844-846 (1989).
6 Murrell, et al., xe2x80x9cA Mutation in the Amyloid Precursor Protein Associated with Hereditary Alzheimer""s Diseasexe2x80x9d, Science, 254:97-99 (1991).
7 Mullan, et al., xe2x80x9cA Pathogenic Mutation for Probable Alzheimer""s Disease in the APP Gene at the N-Terminus of xcex2-Amyloid, Nature Genet., 1:345-347 (1992).
8 Schenk, et al., xe2x80x9cMethods and Compositions for the Detection of Soluble xcex2-Amyloid Peptidexe2x80x9d, International Patent Application Publication No. WO 94/10569, published May 11, 1994.
9 Selkoe, xe2x80x9cAmyloid Protein and Alzheimer""s Diseasexe2x80x9d, Scientific American, pp. 2-8, November, 1991.
10 Tetrahedron Letters, 34(48), 7685 (1993)
11 Losse, et al., Tetrahedron, 27:1423-1434 (1971)
12 Citron, et al., xe2x80x9cMutation of the xcex2-Amyloid Precursor Protein in Familial Alzheimer""s Disease Increases xcex2-Protein Production, Nature, 360:672-674 (1992).
13 Hansen, et al., xe2x80x9cReexamination and Further Development of a Precise and Rapid Dye Method for Measuring Cell Growth/Cell Killxe2x80x9d, J. Immun. Meth., 119:203-210 (1989).
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
Alzheimer""s Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down""s Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the xcex2-amyloid peptide (xcex2AP) or sometimes Axcex2, Axcex2P or xcex2/A4. xcex2-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al.1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,82922.
Molecular biological and protein chemical analyses have shown that the xcex2-amyloid peptide is a small fragment of a much larger precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans. Knowledge of the structure of the gene encoding the APP has demonstrated that xcex2-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s). The precise biochemical mechanism by which the xcex2-amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown.
Several lines of evidence indicate that progressive cerebral deposition of xcex2-amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe3. The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate, et al.4; Chartier Harlan, et al.5; and Murrell, et al.6) and is referred to as the Swedish variant. A double mutation changing lysine595-methionine596 to asparagine595-leucine596 (with reference to the 695 isoform) found in a Swedish family was reported in 1992 (Mullan, et al.7). Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. In addition, a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the xcex2-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its xcex2-amyloid peptide fragment can cause AD.
Despite the progress which has been made in understanding the underlying mechanisms of AD and other xcex2-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting xcex2-amyloid peptide release and/or its synthesis in vivo.
This invention is directed to the discovery of a class of compounds which inhibit xcex2-amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of AD in patients suscepitble to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition. The class of compounds having the described properties are defined by formula I below:
A-B-C
wherein A is selected from the group consisting of: 
where R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
Z is selected from the group consisting of
(a) a group having the formula xe2x80x94CXxe2x80x2Xxe2x80x3C(O)xe2x80x94 where Xxe2x80x2 is hydrogen, hydroxy or fluoro; Xxe2x80x3 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group;
(b) a group having the formula xe2x80x94Txe2x80x94CXxe2x80x2Xxe2x80x3C(O)xe2x80x94 where T is selected from the group consisting of oxygen, sulfur and xe2x80x94NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; Xxe2x80x2 is hydrogen or fluoro, Xxe2x80x3 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group; and
(c) a group having the formula xe2x80x94CXxe2x80x2Xxe2x80x3xe2x80x94Txe2x80x94C(O)xe2x80x94 where T is selected from the group consisting of oxygen, sulfur and xe2x80x94NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; Xxe2x80x2 is hydrogen or fluoro, Xxe2x80x3 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group;
R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
R6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
m is an integer equal to 0 or 1; and
p is an integer equal to 0 or 1; 
xe2x80x83where Rxe2x80x2 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
Txe2x80x2 is selected from the group consisting of a bond covalently linking R1 to xe2x80x94CXxe2x80x2Xxe2x80x3xe2x80x94, oxygen, sulfur and xe2x80x94NR3 where R3 is hydrogen, acyl, alky, aryl or heteroaryl group;
W and X are independently selected from the group consisting of xe2x80x94(CR7R7)qxe2x80x94, oxygen, sulfur and xe2x80x94NR8 where q is an integer equal to one or two, and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation;
and with the further proviso that when W is oxygen, then X is not also oxygen;
Xxe2x80x2 is hydrogen, hydroxy or fluoro, Xxe2x80x3 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group;
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; and 
xe2x80x83where R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
Txe2x80x2 is selected from the group consisting of a bond covalently linking R1 to xe2x80x94CXxe2x80x2Xxe2x80x3xe2x80x94, oxygen, sulfur and xe2x80x94NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group;
W and X are independently selected from the group consisting of xe2x80x94(CR7R7)qxe2x80x94, oxygen, sulfur and xe2x80x94NR8 where q is an integer equal to one or two and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation;
Xxe2x80x2 is hydrogen, hydroxy or fluoro, Xxe2x80x3 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group;
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic;
B is selected from the group consisting of: 
xe2x80x83where R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; 
W and X are independently selected from the group consisting of xe2x80x94(CR7R7)qxe2x80x94, oxygen, sulfur and xe2x80x94NR8 where q is an integer equal to one or two, and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation;
and with the further proviso that when W is oxygen, then X is not also oxygen;
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; 
W and X are independently selected from the group consisting of xe2x80x94(CR7R7)qxe2x80x94, oxygen, sulfur and xe2x80x94NR8 where q is an integer equal to 1 or 2 and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation;
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; and
(iv) when A is either formula (ii) or (iii) as defined above, then B can also be a covalent bond linking A to C;
C is selected from the group consisting of:
xe2x80x94C(O)Y or xe2x80x94-C(S)Yxe2x80x83xe2x80x83(i)
where Y is selected from the group consisting of:
(a) alkyl or cycloalkyl,
(b) substituted alkyl with the proviso that the substitution on said substituted alkyl does not include xcex1-haloalkyl, xcex1-diazoalkyl, xcex1-OC(O)alkyl, or xcex1-OC(O)aryl groups,
(c) alkoxy or thioalkoxy,
(d) substituted alkoxy or substituted thioalkoxy,
(e) hydroxy,
(f) aryl,
(g) heteroaryl,
(h) heterocyclic,
(i) xe2x80x94NRxe2x80x2Rxe2x80x3 where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of Rxe2x80x2 or Rxe2x80x3 is hydroxy or alkoxy, and where Rxe2x80x2 and Rxe2x80x3 are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups,
(j) xe2x80x94NHSO2xe2x80x94R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
(k) xe2x80x94NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and
(1) xe2x80x94ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above;
xe2x80x94CR11R11Yxe2x80x2xe2x80x83xe2x80x83(ii)
where each R11 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic and Yxe2x80x2 is selected from the group consisting of hydroxyl, alkoxy, amino, thiol, substituted alkoxy, thioalkoxy, substituted thioalkoxy, xe2x80x94OC(O)R9, xe2x80x94SSR9, and xe2x80x94SSC(O)R9 where R9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic; and 
where A, together with xe2x80x94C=Nxe2x80x94, forms a heterocyclic group which is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic, xe2x80x94NHC(O)R10, xe2x80x94NHSO2R10, xe2x80x94C(O)NH2, xe2x80x94C(O)NHR10, xe2x80x94C(O)NR10R10, xe2x80x94S(O)R10, xe2x80x94S(O)2R10, xe2x80x94S(O)2NHR10 and xe2x80x94S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N,N-disubstituted alkylamino, N-alkenylamino, N,N-dialkenylamino, N-substituted alkenylamino, N,N-disubstituted alkenylamino, N-cycloalkylamino, N,N-dicycloalkylamino, N-substituted cycloalkylamino, N,N-disubstituted cycloalkylamino, N-arylamino, N,N-diarylamino, N-heteroarylamino, N,N-diheteroarylamino, N-heterocyclic amino, N,N-diheterocyclic amino and mixed N,N-amino groups comprising a first and second substituent on said amino group which substituents are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic provided that said first and second substituents are not the same;
with the proviso that when A has structure (i) and B has structure (i), then C does not have structure (i) or (ii);
with the further provisos that
A. when A has structure (i) with R1 being phenyl, Z being xe2x80x94CH2OC(O)xe2x80x94, R2 being methyl and p being zero, B has structure (iii) with W being xe2x80x94NHxe2x80x94, X being xe2x80x94CH2xe2x80x94, and R4 being benzyl then C is not xe2x80x94C(O)OCH3;
B. when A has structure (i) with R1 being 3,5-difluorophenyl, Z being xe2x80x94CH2C(O)xe2x80x94, R2 being methyl, and p being zero, B has structure (ii) with W being  greater than NC(O)OC(CH3)3, X being xe2x80x94CH2xe2x80x94, and R4 being phenyl, then C is not xe2x80x94C(O)OCH3; and
C. when A has structure (ii) wherein R1 is 3,5-difluorophenyl, Txe2x80x2 is a bond linking R1 to xe2x80x94CXxe2x80x2Xxe2x80x3xe2x80x94, Xxe2x80x2 and Xxe2x80x3 are hydrogen, W is sulfur, X is methylene and R4 is methyl, and B is a covalent bond linking A to C, then C is not xe2x80x94C(O)OCH3.
In one preferred embodiment, the compounds of formula I are further characterized by formula II below: 
wherein R1, R2, R5, R6, A, Z, m and p are as defined above.
In formula II above, when m is one, Z is preferably xe2x80x94CXxe2x80x2Xxe2x80x3C(O)xe2x80x94 where Xxe2x80x3 is preferably hydrogen, Xxe2x80x2 is preferably hydrogen or fluoro or Xxe2x80x2 and Xxe2x80x3 form an oxo group.
In formula II above, preferred R1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like.
Preferred Rxe2x80x2 substituted aryl groups in formula II include, for example, monosubstituted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3,5 substituents); and trisubstituted phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not include more than 3 substituents.
Examples of substituted R1 phenyls preferred in formula II include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl.
Preferred R1 alkaryl groups in formula II include, by way of example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, and the like.
Preferred R1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups in formula II include, by way of example, iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2-cyclopentyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclobutyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2CH2-cyclopentyl, and the like.
Preferred R1 heteroaryls and substituted heteroaryls in formula II include, by way of example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, and the like.
Preferably, in formula II, R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. Particularly preferred R2 substituents include, by way of example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, xe2x80x94CH2CH2SCH3, and the like. As noted below, R2, as well as R5 and R6 are preferably the side chain of an L-amino acid.
Preferred R5 and/or R6 substituents in formula II are independently selected from the group consisting of include, for example, hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, xe2x80x94CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholinoxe2x80x94CH2CH2O)-benzyl, xe2x80x94CH2CH2C(O)NH2, xe2x80x94CH2-imidazol-4-yl, xe2x80x94CH2-(3-tetrahydrofuranyl), xe2x80x94CH2-thiophen-2-yl, xe2x80x94CH2(1-methyl)cyclopropyl, xe2x80x94CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, xe2x80x94CH2xe2x80x94C(O)O-t-butyl, xe2x80x94CH2xe2x80x94C(CH3)3, xe2x80x94CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, xe2x80x94CH[CH(CH3)2] COOCH3, xe2x80x94CH2CH2N(CH3)2, xe2x80x94CH2C(CH3)xe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CHCH3 (cis and trans), xe2x80x94CH2OH, xe2x80x94CH(OH)CH3, xe2x80x94CH(O-t-butyl)CH3, xe2x80x94CH2OCH3, xe2x80x94(CH2)4NH-Boc, xe2x80x94(CH2)4NH2, xe2x80x94CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), xe2x80x94CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), xe2x80x94CH2-(N-morpholino), p-(N-morpholinoxe2x80x94CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, xe2x80x94CH2CH2SCH3, thien-2-yl, thien-3-yl, and the like.
In formula II, preferred 
groups are further characterized by the following structures: 
where Yxe2x80x3 is a heteroatom selected from oxygen, sulfur and  greater than NR8 where R8 is as defined above and Axe2x80x2, together with xe2x80x94Yxe2x80x3xe2x80x94Cxe2x95x90Nxe2x80x94, forms a heterocyclic group which is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloallyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, aryl, heteroaryl, heterocyclic, xe2x80x94NHC(O)R10, xe2x80x94NHSO2R10, xe2x80x94C(O)NH2, xe2x80x94C(O)NHR10, xe2x80x94C(O)NR10R10, xe2x80x94S(O)R10, xe2x80x94S(O)2R10, xe2x80x94S(O)2NHR10 and xe2x80x94S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl.
Preferred heterocyclic structures include, by way of example, 3-methyl-1,2,4-oxadiazol-5-yl, thiazolin-2-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 3-(p-methoxy-benzyl)-1,2,4-oxadiazol-5-yl, and the like.
Preferred compounds of formula II include the following:
(S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino]ethyl-3-ethyl-1,2,4-oxadiazole
(S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2-phenylethyl]-3-methyl-1,2,4-oxadiazole
2-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-2-thiazoline
(S)-5- [1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-3-methyl-1,2,4-oxadiazole
(S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-3-phenyl-1,2,4-oxadiazole
(S)-5-[1-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-phenyl]methyl-3-(4-methoxyphenylmethyl)-1,2,4-oxadiazole
In another preferred embodiment, the compounds of formula I are further characterized by formula III and IV below: 
wherein R1, R2, R4, R6, W, X, Y, Z, m and p are as defined above.
In formula III and IV above, when m is one, Z is preferably xe2x80x94CXxe2x80x2Xxe2x80x3C(O)xe2x80x94 where Xxe2x80x3 is preferably hydrogen, Xxe2x80x2 is preferably hydrogen or fluoro and where Xxe2x80x2 and Xxe2x80x3 form an oxo group.
In formula III and IV above, preferred R1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like.
Preferred R1 substituted aryl groups in formula III and IV include, for example, monosubstituted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3,5 substituents); and trisubstituted phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not include more than 3 substituents.
Examples of substituted R1 phenyls preferred in formula III and IV include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl.
Preferred R1 alkaryl groups in formula III and IV include, by way of example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, and the like.
Preferred R1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups in formula III and IV include, by way of example, iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2-cyclopentyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclobutyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2CH2-cyclopentyl, and the like.
Preferred R1 heteroaryls and substituted heteroaryls in formula III and IV include, by way of example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, and the like.
Preferably, in formula III and IV, R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. Particularly preferred R2 substituents include, by way of example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, xe2x80x94CH2CH2SCH3, and the like. As noted below, R2 (as well as R6) are preferably the side chain of an L-amino acid.
Preferred R6 substituents in formula III and IV include, for example, hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, xe2x80x94CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholinoxe2x80x94CH2CH2O)-benzyl, xe2x80x94CH2CH2C(O)NH2, xe2x80x94CH2-imidazol-4-yl, xe2x80x94CH2-(3-tetrahydrofuranyl), xe2x80x94CH2-thiophen-2-yl, xe2x80x94CH2(1-methyl)cyclopropyl, xe2x80x94CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, xe2x80x94CH2xe2x80x94C(O)O-t-butyl, xe2x80x94CH2xe2x80x94C(CH3)3, xe2x80x94CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, xe2x80x94CH[CH(CH3)2]COOCH3, xe2x80x94CH2CH2N(CH3)2, xe2x80x94CH2C(CH3)xe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CHCH3 (cis and trans), xe2x80x94CH2OH, xe2x80x94CH(OH)CH3, xe2x80x94CH(O-t-butyl)CH3, xe2x80x94CH2OCH3, xe2x80x94(CH2)4NH-Boc, xe2x80x94(CH2)4NH2, xe2x80x94CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), xe2x80x94CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), xe2x80x94CH2-(N-morpholino), p-(N-morpholinoxe2x80x94CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5 ,6,7-tetrahydrobenzo [b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, xe2x80x94CH2CH2SCH3, thien-2-yl, thien-3-yl, and the like.
Preferably Y in Formula III or IV is hydroxy, alkoxy, substituted alkoxy and xe2x80x94NRxe2x80x2Rxe2x80x3 where Rxe2x80x2 and Rxe2x80x3 are as defined above. Preferred alkoxy and substituted alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, and the like. Preferred xe2x80x94NRxe2x80x2Rxe2x80x3 groups include, by way of example, amino (xe2x80x94NH2), xe2x80x94NH(iso-butyl), xe2x80x94NH(sec-butyl), N-methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino, N-heptamethylene-imino, N-pyrrolidinyl, xe2x80x94NH-methallyl, xe2x80x94NHCH2-(furan-2-yl), xe2x80x94NHCH2-cyclopropyl, xe2x80x94NH(t-butyl), xe2x80x94NH(p-methylphenyl), xe2x80x94NHOCH3, xe2x80x94NHCH2(p-fluorophenyl), xe2x80x94NHCH2CH2OCH3, xe2x80x94NH-cyclohexyl, xe2x80x94NHCH2CH2N(CH3)2, xe2x80x94NHCH2C(CH3)3, xe2x80x94NHCH2-(pyrid-2-yl), xe2x80x94NHCH2-(pyrid-3-yl), xe2x80x94NHCH2-(pyrid-4-yl), N-thiazolindinyl, xe2x80x94N(CH2CH2CH3)2, xe2x80x94NHOH, xe2x80x94NH(p-NO2-xcfx86), xe2x80x94NHCH2(p-NO2-xcfx86), xe2x80x94NHCH2(m-NO2-xcfx86), xe2x80x94N(CH3)OCH3, xe2x80x94N(CH3)CH2-xcfx86, xe2x80x94NHCH2-(3,5-di-fluorophenyl), xe2x80x94NHCH2CH2F, xe2x80x94NHCH2(p-CH3O-xcfx86), xe2x80x94NHCH2(m-CH3O-xcfx86), xe2x80x94NHCH2(p-CF3-xcfx86), xe2x80x94N(CH3)CH2CH2OCH3, xe2x80x94NHCH2CH2xcfx86, xe2x80x94NHCH(CH3)xcfx86, xe2x80x94NHCH2-(p-F-xcfx86), xe2x80x94N(CH3)CH2CH2N(CH3)2, xe2x80x94NHCH2-(tetrahydrofuran-2-yl), and the like.
Still another preferred Y group is an alkyl group such as xe2x80x94CH2CH2CH(CH3)2, and the like.
Preferred heterocyclic structures defined by W and X include, by way of example, 4,5-dihydrothiazoles, 3,4-dihydro-1,3-isodiazoles, 3,4-dihydro-3-N-t-butoxy-3-isodiazoles, 4,5-dihydrooxazoles, and the like.
Preferred compounds of formula III and IV include the following:
(S)-2-[1-(3,5-difluorophenylacetamido)ethyl]-4-ethoxycarbonyl-2-thiazoline
1-tert-butoxycarbonyl-2-[1-(N-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline
1-tert-butoxycarbonyl-2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline
2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline
2-[1-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline
2-[1-(3,5-difluorophenylacetamido)-1-phenyl]methyl-4-ethoxycarbonyl-2-thiazoline
1-ter-butoxycarbonyl-2-[1-(N-carbobenzyloxy)aminoethyl]4-methoxycarbonyl-4-phenyl-2-imidazoline
2-[(S)-1-(3,5-dichloroanilino)ethyl]-(S)-4-methoxycarbonyl-2-oxazolidine
(S)-2-[1-(3,5-difluorophenylacetamido)ethyl]-5(R,S)-ethoxycarbonyl-2-oxazoline
2-[1-(3,5-difluorophenylacetamido)-1-phenyl]methyl-4-methoxycarbonyl-2-thiazoline
[1-(N-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline
In another preferred embodiment, the compounds of formula I are further characterized by formula V and VI below: 
where R1, R4, R6, Txe2x80x2, Xxe2x80x2, Xxe2x80x3, W, X, and Y are as defined above.
In formula V and VI above, when m is one, Z is preferably xe2x80x94CXxe2x80x2Xxe2x80x3C(O)xe2x80x94 where Xxe2x80x3 is preferably hydrogen, Xxe2x80x2 is preferably hydrogen or fluoro or where Xxe2x80x2 and Xxe2x80x3 form an oxo group.
In formula V and VI above, preferred R1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like.
Preferred R1 substituted aryl groups in formula V and VI include, for example, monosubstituted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3,5 substituents); and trisubstituted phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not include more than 3 substituents.
Examples of substituted R1 phenyls preferred in formula IV and VI include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl.
Preferred R1 alkaryl groups in formula IV and VI include, by way of example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, and the like.
Preferred R1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups in formula V and VI include, by way of example, iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2-cyclopentyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclobutyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2CH2-cyclopentyl, and the like.
Preferred R1 heteroaryls and substituted heteroaryls in formula III and IV include, by way of example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, and the like.
Preferred R4 substituents in formula III and IV include, for example, hydrogen, methyl, phenyl, benzyl and the like.
Preferred R6 substituents in formula V and VI include, for example, hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, xe2x80x94CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholinoxe2x80x94CH2CH2O)-benzyl, xe2x80x94CH2CH2C(O)NH2, xe2x80x94CH2-imidazol-4-yl, xe2x80x94CH2-(3-tetrahydrofuranyl), xe2x80x94CH2-thiophen-2-yl, xe2x80x94CH2(1-methyl)cyclopropyl, xe2x80x94CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, xe2x80x94CH2xe2x80x94C(O)O-t-butyl, xe2x80x94CH2xe2x80x94C(CH3)3, xe2x80x94CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, xe2x80x94CH[CH(CH3)2]COOCH3, xe2x80x94CH2CH2N(CH3)2, xe2x80x94CH2C(CH3)xe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CHCH3 (cis and trans), xe2x80x94CH2OH, xe2x80x94CH(OH)CH3, xe2x80x94CH(O-t-butyl)CH3, xe2x80x94CH2OCH3, xe2x80x94(CH2)4NH-Boc, xe2x80x94(CH2)4NH2, xe2x80x94CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), xe2x80x94CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), xe2x80x94CH2-(N-morpholino), p-(N-morpholinoxe2x80x94CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, xe2x80x94CH2CH2SCH3, thien-2-yl, thien-3-yl, and the like.
Preferably Y in Formula V or VI is hydroxy, alkoxy, substituted alkoxy and xe2x80x94NRxe2x80x2Rxe2x80x3 where Rxe2x80x2 and Rxe2x80x3 are as defined above. Preferred alkoxy and substituted alkoxy groups include methoxy, ethyoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, and the like. Preferred xe2x80x94NRxe2x80x2Rxe2x80x3 groups include, by way of example, amino (xe2x80x94NH2), xe2x80x94NH(iso-butyl), xe2x80x94NH(sec-butyl), N-methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino, N-heptamethylene-imino, N-pyrrolidinyl, xe2x80x94NH-methallyl, xe2x80x94NHCH2-(furan-2-yl), xe2x80x94NHCH2-cyclopropyl, xe2x80x94NH(t-butyl), xe2x80x94NH(p-methylphenyl), xe2x80x94NHOCH3, xe2x80x94NHCH2(p-fluorophenyl), xe2x80x94NHCH2CH2OCH3, xe2x80x94NH-cyclohexyl, xe2x80x94NHCH2CH2N(CH3)2, xe2x80x94NHCH2C(CH3)3, xe2x80x94NHCH2-(pyrid-2-yl), xe2x80x94NHCH2-(pyrid-3-yl), xe2x80x94NHCH2-(pyrid-4-yl), N-thiazolindinyl, xe2x80x94N(CH2CH2CH3)2, xe2x80x94NHOH, xe2x80x94NH(p-NO2-xcfx86), xe2x80x94NHCH2(p-NO2-xcfx86), xe2x80x94NHCH2(m-NO2xcfx86), xe2x80x94N(CH3)OCH3, xe2x80x94N(CH3)CH2-xcfx86), xe2x80x94NHCH2-(3,5-di-fluorophenyl), xe2x80x94NHCH2CH2F, xe2x80x94NHCH2(p-CH3O-xcfx86), xe2x80x94NHCH2(m-CH3O-xcfx86), xe2x80x94NHCH2(p-CF3-xcfx86), xe2x80x94N(CH3)CH2CH2OCH3, xe2x80x94NHCH2CH2xcfx86, xe2x80x94NHCH(CH3)xcfx86, xe2x80x94NHCH2-(p-F-xcfx86), xe2x80x94N(CH3)CH2CH2N(CH3)2, xe2x80x94NHCH2-(tetrahydrofuran-2-yl), and the like.
Still another preferred Y group is an alkyl group such as xe2x80x94CH2CH2CH(CH3)2, and the like.
Preferred heterocyclic structures defined by W and X include, by way of example, 4-methylthiazolin-4-yl.
Preferred compounds of formula V and VI include the following:
(4R)-4-[N-(1S)-(1-methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-4-methyl-2-thiazoline
4-[N-(S)-(1-methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-2-thiazoline
4-[N-(S)-(1-methoxycarbonyl-1-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-4-methyl-2-imidazoline
Yet another preferred compound of this invention includes lactams and related compounds of formula VII and VIII 
wherein R1, R4, R6, Txe2x80x2, Xxe2x80x2, Xxe2x80x3, W and X are as defined above;
Wxe2x80x2, together with xe2x80x94C(H)sC(xe2x95x90U)xe2x80x94, forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, xe2x80x94NHC(O)R10, xe2x80x94NHSO2R10, xe2x80x94C(O)NH2, xe2x80x94C(O)NHR10, xe2x80x94C(O)NR10R10, xe2x80x94S(O)R10, xe2x80x94S(O)2R10, xe2x80x94S(O)2NHR10 and xe2x80x94S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl;
U is selected from the group consisting of oxo (xe2x95x90O), thiooxo (xe2x95x90S), hydroxyl (xe2x80x94H, xe2x80x94OH), thiol (H,xe2x80x94SH) and hydro (H,H);
s is an integer equal to 0 or 1; and
t is an integer equal to 0 or 1.
In formula VII and VIII above, Xxe2x80x3 is preferably hydrogen, Xxe2x80x2 is preferably hydrogen or fluoro or Xxe2x80x2 and Xxe2x80x3 form an oxo group, and Txe2x80x2 is preferably a covalent bond linking R1 to xe2x80x94CXxe2x80x2Xxe2x80x3xe2x80x94.
In formula VII and VIII above, preferred R1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like.
Preferred R1 substituted aryl groups in formula VII and VIII include, for example, monosubstituted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3,5 substituents); and tnisubstituted phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not include more than 3 substituents.
Examples of substituted R1 phenyls preferred in formula VII and VIII include 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl.
Preferred R1 alkaryl groups in formula VII and VIII include, by way of example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, and the like.
Preferred R1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups in formula VII and VIII include, by way of example, iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2-cyclopentyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94C112CH2-cyclobutyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2CH2-cyclopentyl, and the like.
Preferred R1 heteroaryls and substituted heteroaryls in formula VII and VIII include, by way of example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, and the like.
Preferred R4 substituents in formula VII and VIII include, for example, hydrogen, methyl, phenyl, benzyl and the like.
Preferred R6 substituents in formula VII and VIII include, for example, hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, xe2x80x94CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholinoxe2x80x94CH2CH2O)-benzyl, xe2x80x94CH2CH2C(O)NH2, xe2x80x94CH2-imnidazol-4-yl, xe2x80x94CH2-(3-tetrahydrofuranyl), xe2x80x94CH2-thiophen-2-yl, xe2x80x94CH2(1-methyl)cyclopropyl, xe2x80x94CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, xe2x80x94CH2xe2x80x94C(O)O-t-butyl, xe2x80x94CH2xe2x80x94C(CH3)3, xe2x80x94CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, xe2x80x94CH[CH(CH3)2]COOCH3, xe2x80x94CH2CH2N(CH3)2, xe2x80x94CH2C(CH3)xe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CHCH3 (cis and trans), xe2x80x94CH2OH, xe2x80x94CH(OH)CH3, xe2x80x94CH(O-t-butyl)CH3, xe2x80x94CH2OCH3, xe2x80x94(CH2)4NH-Boc, xe2x80x94(CH2)4NH2, xe2x80x94CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), xe2x80x94CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), xe2x80x94CH2-(N-morpholino), p-(N-morpholinoxe2x80x94CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, xe2x80x94CH2CH2SCH3, thien-2-yl, thien-3-yl, and the like.
Preferred cyclic groups defined by Wxe2x80x2 and xe2x80x94C(H)sC(xe2x95x90U)xe2x80x94 include cycloalkyl, lactone, lactam, benzazepinone, dibenzazepinone and benzodiazepine groups. In one preferred embodiment, the cyclic group defined by Wxe2x80x2 and xe2x80x94C(H)sC(xe2x95x90U)xe2x80x94, forms a cycloalkyl group of the formula: 
wherein Txe2x80x3 is selected from the group consisting of alkylene and substituted alkylene.
A preferred cycloalkyl group is represented by the formula: 
wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
In another preferred embodiment, the cyclic group defined by Wxe2x80x2, together with xe2x80x94C(H)sC(xe2x95x90U)xe2x80x94 is a ring of the formula: 
wherein s is zero or one, Txe2x80x3 is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, xe2x80x94(R13Z)qR13xe2x80x94 and xe2x80x94ZR13xe2x80x94 where Z is a substituent selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and  greater than NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and q is an integer of from 1 to 3.
Particularly preferred alcohol or thiol substituted groups include 
wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
Yet another preferred embodiment of the cyclic group defined by Wxe2x80x2, together with xe2x80x94C(H)sC(xe2x95x90U)xe2x80x94, is a ring of the formula: 
wherein s is zero or one, Txe2x80x3 is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, xe2x80x94(R13Z)qR13xe2x80x94 and xe2x80x94ZR13xe2x80x94where Z is a substituent selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and  greater than NR12, each R12 is independently selected from the group consisting of alky, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and q is an integer of from 1 to 3.
Particularly preferred cyclic ketone and thioketone groups include: 
wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
In another preferred embodiment, the cyclic group defined by Wxe2x80x2, together with xe2x80x94C(H)sC(xe2x95x90U)xe2x80x94, forms a ring of the formula: 
wherein s is zero or one, Txe2x80x3 is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, xe2x80x94(R13Z)qR13xe2x80x94 and xe2x80x94ZR13xe2x80x94where Z is a substituent selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and  greater than NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and q is an integer of from 1 to 3.
Particularly preferred lactone and thiolactone groups include: 
wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1.
In another preferred embodiment, the cyclic group defined by Wxe2x80x2 and xe2x80x94C(H)sC(xe2x95x90U)xe2x80x94, forms a lactam ring of the formula: 
or a thiolactam ring of the formula: 
wherein s is zero or one, Txe2x80x3 is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, xe2x80x94(R13Z)qR13xe2x80x94 and xe2x80x94ZR13xe2x80x94where Z is a substituent selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and  greater than NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and q is an integer of from 1 to 3.
Particularly preferred lactam and thiolactam groups include: 
wherein A-B is selected from the group consisting of alkylene, alkenylene, substituted alkylene, substituted alkenylene and xe2x80x94Nxe2x95x90CHxe2x80x94; Qxe2x80x2 is oxygen or sulfur; each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; Rb is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl, heterocyclic, and the like; Rc is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; txe2x80x2 is an integer from 0 to 3; and w is an integer from 0 to 3.
Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to O or 1.
In another preferred embodiment, the cyclic group defined by Wxe2x80x2, together with xe2x80x94C(H)sC(xe2x95x90U)xe2x80x94, forms a ring of the formula: 
wherein s is zero or one, Txe2x80x3 is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, xe2x80x94(R13Z)qR13xe2x80x94 and xe2x80x94ZR13xe2x80x94 where Z is a substituent selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and  greater than NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and q is an integer of from 1 to 3.
A still further preferred embodiment is directed to a ring group defined by W, together with xe2x80x94C(H)sC(xe2x95x90U)xe2x80x94, of the formula: 
wherein s is zero or one, Txe2x80x3 is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, xe2x80x94(R13Z)qR13xe2x80x94 and xe2x80x94ZR13xe2x80x94 where Z is a substituent selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and  greater than NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, and q is an integer of from 1 to 3.
Yet another preferred compound of this invention includes lactams and related compounds of formula IX and X: 
wherein R1, R2, R4, Z, U, W, Wxe2x80x2, X, m and S are as defined above.
Preferred R1, R2, R4, Z, W and Wxe2x80x2 are also as defined above.
In one of its method aspects, this invention is directed to a method for inhibiting xcex2-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds of formula I, VII and VIII above effective in inhibiting the cellular release and/or synthesis of xcex2-amyloid peptide.
Because the in vivo generation of xcex2-amyloid peptide is associated with the pathogenesis of AD8.9, the compounds of formula I, VII and VIII can also be employed in conjunction with a pharmaceutical composition to prophylactically and/or therapeutically prevent and/or treat AD. Accordingly, in another of its method aspects, this invention is directed to a prophylactic method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I, VII and VIII above.
In yet another of its method aspects, this invention is directed to a therapeutic method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I, VII and VIII above.
This invention also provides for novel pharmaceutical compositions comprising a pharmaceutically inert carrier and a compound of the formula I, VII or VIII above.
Still further, this invention provides for novel compounds of formula I, VII or VIII.
Further preferred compounds of formula I are represented in the following Tables I-IV which illustrate preferred subsets of these structures:
As above, this invention relates to compounds which inhibit xcex2-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer""s disease. However, prior to describing this invention in further detail, the following terms will first be defined.
Definitions
The term xe2x80x9cxcex2-amyloid peptidexe2x80x9d refers to a 39-43 amino acid peptide having a molecular weight of about 4.2 kD, which peptide is substantially homologous to the form of the protein described by Glenner, et al.1 including mutations and post-translational modifications of the normal xcex2-amyloid peptide. In whatever form, the xcex2-amyloid peptide is an approximate 39-43 amino acid fragment of a large membrane-spanning glycoprotein, referred to as the xcex2-amyloid precursor protein (APP). Its 43-amino acid sequence is:
1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr
11 Glu Val His His Gln Lys Leu Val Phe Phe
21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala
31 Ile Ile Gly Leu Met Val Gly Gly Val Val
41 Ile Ala Thr (SEQ ID NO: 1) or a sequence which is substantially homologous thereto.
xe2x80x9cAlkylxe2x80x9d refers to monovalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like.
xe2x80x9cSubstituted alkylxe2x80x9d refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxylalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, aryloxy, thioaryloxy, heteroaryloxy, thioheteroaryloxy, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
xe2x80x9cAlkylenexe2x80x9d refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), the propylene isomers (e.g., xe2x80x94CH2CH2CH2xe2x80x94 and xe2x80x94CH(CH3)CH2xe2x80x94), and the like.
xe2x80x9cAlkarylxe2x80x9d refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
xe2x80x9cAlkoxyxe2x80x9d refers to the group xe2x80x9calkylxe2x80x94Oxe2x80x94xe2x80x9d. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
xe2x80x9cSubstituted alkoxyxe2x80x9d refers to the group xe2x80x9csubstituted alkylxe2x80x94Oxe2x80x94xe2x80x9d where substituted alkyl is as defined above.
xe2x80x9cAlkenylxe2x80x9d refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (xe2x80x94CHxe2x95x90CH2), n-propenyl (xe2x80x94CH2CHxe2x95x90CH2), iso-propenyl (xe2x80x94C(CH3)xe2x95x90CH2), but-2-enyl (xe2x80x94CH2CHxe2x95x90CHCH3), and the like.
xe2x80x9cSubstituted alkenylxe2x80x9d refers to an alkenyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
xe2x80x9cAlkenylenexe2x80x9d refers to divalent alkenylene groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. This term is exemplified by groups such as ethenylene (xe2x80x94CHxe2x95x90CHxe2x80x94), the propenylene isomers (e.g., xe2x80x94CH2CHxe2x95x90CHxe2x80x94 and xe2x80x94C(CH3)xe2x95x90CHxe2x80x94) and the like.
xe2x80x9cSubstituted alkenylenexe2x80x9d refers to an alkenylene group, preferably of from 2 to 8 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic. Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group.
xe2x80x9cAlkynylxe2x80x9d refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (xe2x80x94Cxe2x89xa1CH), propargyl (xe2x80x94CH2Cxe2x89xa1CH) and the like.
xe2x80x9cSubstituted alkynylxe2x80x9d refers to an alkynyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkyoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
xe2x80x9cAcylxe2x80x9d refers to the groups alkyl-C(O)xe2x80x94, substituted alkyl-C(O)xe2x80x94, cycloalkyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, heteroaryl-C(O)xe2x80x94 and heterocyclic-C(O)xe2x80x94 where alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cAcylaminoxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cAminoacylxe2x80x9d refers to the group xe2x80x94NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cOxyacylxe2x80x9d refers to the groups xe2x80x94OC(O)-alkyl, xe2x80x94OC(O)-aryl, xe2x80x94C(O)O-heteroaryl-, and xe2x80x94C(O)O-heterocyclic where alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cOxyacylaminoxe2x80x9d refers to the groups xe2x80x94OC(O)NR-alkyl, xe2x80x94OC(O)NRxe2x80x94 substituted alkyl, xe2x80x94OC(O)NR-aryl, xe2x80x94OC(O)NR-heteroaryl-, and xe2x80x94OC(O)NR-heterocyclic where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cAminocarboxy estersxe2x80x9d refers to the groups xe2x80x94NRC(O)O-alkyl, xe2x80x94NRC(O)O-substituted alkyl, xe2x80x94NRC(O)O-aryl, xe2x80x94NRC(O)O-heteroaryl, and xe2x80x94NRC(O)O-heterocyclic where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cArylxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, acylamino, cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
xe2x80x9cAryloxyxe2x80x9d refers to the group aryl-Oxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
xe2x80x9cCarboxyalkylxe2x80x9d refers to the groups xe2x80x94C(O)O-alkyl and xe2x80x94C(O)O-substituted alkyl where alkyl and substituted alkyl are as defined above.
xe2x80x9cCycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 8 carbon atoms having a single cyclic ring or multiple condensed rings which can be optionally substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
xe2x80x9cSubstituted cycloalkylxe2x80x9d refers to cycloalkyl groups having from 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like.
xe2x80x9cCycloalkenylxe2x80x9d refers to cyclic alkenyl groups of from 4 to 8 carbon atoms having a single cyclic ring and at least one point of internal unsaturation which can be optionally substituted with from 1 to 3 alkyl groups. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
xe2x80x9cSubstituted cycloalkenylxe2x80x9d refers to cycloalkenyl groups having from 1 to 5 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo and preferably is either chloro or bromo.
xe2x80x9cHeteroarylxe2x80x9d refers to a monovalent aromatic carbocyclic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring.
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsynumetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, and the like. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include morpholino, piperidinyl, and the like.
Examples of heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.
xe2x80x9cOxyacylxe2x80x9d refers to the groups xe2x80x94OC(O)-alkyl, xe2x80x94OC(O)-aryl, xe2x80x94C(O)Oxe2x80x94heteroaryl-, and xe2x80x94C(O)O-heterocyclic where alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cOxyacylaminoxe2x80x9d refers to the groups xe2x80x94OC(O)NH-alkyl, xe2x80x94OC(O)NHxe2x80x94substituted alkyl, xe2x80x94OC(O)NH-aryl, xe2x80x94OC(O)NH-heteroaryl-, and xe2x80x94OC(O)NHxe2x80x94heterocyclic where alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cThiolxe2x80x9d refers to the group xe2x80x94SH.
xe2x80x9cThioalkoxyxe2x80x9d refers to the group xe2x80x94S-alkyl.
xe2x80x9cSubstituted thioalkoxyxe2x80x9d refers to the group xe2x80x94S-substituted alkyl.
xe2x80x9cThioaryloxyxe2x80x9d refers to the group aryl-Sxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
xe2x80x9cThioheteroaryloxyxe2x80x9d refers to the group heteroaryl-Sxe2x80x94 wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to pharmaceutically acceptable salts of a compound of formula I, VII or VIII which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
Compound Preparation
The compounds of formula I are readily prepared via several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, commercial availability of starting materials, etc.
The heterocyclic ring(s) in the compounds of formula I above can be prepared by use or adaptation of known chemical syntheses and methods, which synthesis and methods are well known in the art. For example, the synthesis of various heterocycles is illustrated in detail in the examples set forth below. Using these procedures, other suitable heterocycles can be prepared by modifying the starting materials employed in these procedures.
In certain cases, the compounds of formula I above are prepared by coupling a suitable heterocycle having one or more pendant functional groups to the other components necessary to form the A-B-C structure of formula I. Typical functional groups used for such couplings include, by way of example, carboxylic acid and amino groups. The coupling reaction is generally conducted using conventional coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to facilitate coupling. The reaction is typically conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.
The compounds of formula VII and VIII are readily prepared by conventional amidation of a carboxylic acid as shown in reaction (1) below: 
wherein R1, R4, R6, Txe2x80x2, Xxe2x80x2, Xxe2x80x3, W, X, Wxe2x80x2, U, t and s are as defined above.
The reaction is conventionally conducted by using at least a stoichiometric amount of carboxylic acid 1a or 1b and amine 2. This reaction is conventionally conducted for peptide synthesis and synthetic methods used therein can also be employed to prepare compounds VII and VIII. For example, well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to facilitate coupling. The reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. Alternatively, the acid halide of compound 1a or 1b can be employed in reaction (1) and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, triethylamine, diisopropylethylamine, N-methylmorpholine and the like.
Synthesis of Carboxylic Acid Starting Materials
Carboxylic acids 1a and 1b can be prepared by several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, commercial availability of starting materials, whether t is zero or one. One method for preparing these compounds (when t is one) is the hydrolysis of esters of compounds of formula V and VI above. Similar methods can be employed to prepare related compounds when t is zero.
Carboxylic acids 1 having m equal to 1 and n equal to 1 or 2 can also be prepared by use of polymer supported forms of carbodiimide peptide coupling reagents. A polymer supported form of EDC, for example, has been described (Tetrahedron Letters, 34(48), 7685 (1993))10. Additionally, a new carbodiimide coupling reagent, PEPC, and its corresponding polymer supported forms have been discovered and are very useful for the preparation of such compounds.
Polymers suitable for use in making a polymer supported coupling reagent are either commercially available or may be prepared by methods well known to the artisan skilled in the polymer arts. A suitable polymer must possess pendant sidechains bearing moieties reactive with the terminal amine of the carbodiimide. Such reactive moieties include chloro, bromo, iodo and methanesulfonyl. Preferably, the reactive moiety is a chloromethyl group. Additionally, the polymer""s backbone must be inert to both the carbodiimide and reaction conditions under which the ultimate polymer bound coupling reagents will be used.
Certain hydroxymethylated resins may be converted into chloromethylated resins useful for the preparation of polymer supported coupling reagents. Examples of these hydroxylated resins include the 4-hydroxymethylphenylacetamidomethyl resin (Pam Resin) and 4-benzyloxybenzyl alcohol resin (Wang Resin) available from Advanced Chemtech of Louisville, Ky., USA (see Advanced Chemtech 1993-1994 catalog, page 115). The hydroxymethyl groups of these resins may be converted into the desired chloromethyl groups by any of a number of methods well known to the skilled artisan.
Preferred resins are the chloromethylated styrene/divinylbenzene resins because of their ready commercial availability. As the name suggests, these resins are already chloromethylated and require no chemical modification prior to use. These resins are commercially known as Merrifield""s resins and are available from Aldrich Chemical Company of Milwaukee, Wis., USA (see Aldrich 1994-1995 catalog, page 899). Methods for the preparation of PEPC and its polymer supported forms are outlined in the following scheme. 
Such methods are described more fully in U.S. patent application Ser. No. 60/019,790 filed Jun. 14, 1996 which application is incorporated herein by reference in its entirety. Briefly, PEPC is prepared by first reacting ethyl isocyanate with 1-(3-aminopropyl)pyrrolidine. The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC. The polymer supported form is prepared by reaction of PEPC with an appropriate resin under standard conditions to give the desired reagent.
The carboxylic acid coupling reactions employing these reagents are performed at about ambient to about 45xc2x0 C., for from about 3 to 120 hours. Typically, the product may be isolated by washing the reaction with CHCl3 and concentrating the remaining organics under reduced pressure. As discussed supra, isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.
Preparation of Cyclic Amino Compounds
Cyclic amino compounds 2 employed in reaction (1) above are generally aminolactams, aminolactones, aminothiolactones and aminocycloalkyl compounds which can be represented by the formula: 
where U and s are as defined above, Q is preferably selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94,  greater than NR16, and  greater than CR17R18 where each of R16, R17 and R18 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic with the proviso that if Q is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or  greater than NR16, then X is oxo or dihydro.
The aminolactams, aminolactones and aminothiolactones of the formula above can be prepared by use or adaptation of known chemical syntheses which syntheses are well described in the literature. See, e.g., Ogliaruso and Wolfe, Synthesis of Lactones and Lactams, Patai, et al. Editor, J. Wiley and Sons, New York, New York, USA, pp. 1085 et seq. (1993).
Specifically, 3-amino substituted lactams 13 with 5, 6 or 7 ring atoms may be prepared by the direct cyclization of a suitable alpha, omega-diamino acid ester 12 as shown in reaction (5) below: 
wherein L is a linking group (typically an alkylene group) of from 2-4 atoms, Pr is a suitable protecting group such as t-butoxycarbonyl, carbobenzyloxy, or the like and R19 is an alkoxy or aryloxy group such as methoxy, ethoxy, p-nitrophenoxy, N-succinimidoxy, and the like. The reaction may be carried out in a solvent such as water, methanol, ethanol, pyridine, and the like. Such reactions are exemplied by cyclization of a lysine ester to a caprolactam as described by Ugi, et al., Tetrahedron, 52(35):11657-11664 (1996). Alternatively, such a cyclization can also be conducted in the presence of dehydrating agents such as alumina or silica to form lactams as described by Blade-Font, Tetrahedron Lett., 21:2443 (1980).
The preparation of aminolactams alkylated on the amino group of the cyclic lactam is described by Freidinger, et al., J. Org. Chem., 47:104-109 (1982) and illustrated in reaction (6) below: 
wherein L and R16 are as defined above.
In reaction (6), reductive amination of 14 with aldehyde 15 and subsequent ring closure by methods using, for example, EDC provides for aminolactam 16. The preparation of six-membered lactams using this general procedure is described by Semple, et al., J. Med. Chem., 39:4531-4536 (1996).
The internal cyclization of an amide anion with a halide or equivalent thereof can sometimes be used to particular advantage in the synthesis of smaller ring lactams where the stereochemistry of the amino-lactam center is available from the standard amino-acid pool. This approach is illustrated in reaction (7) below: 
where R16 is as defined above.
The approach of reaction (7) is presented by Semple, et al., supra., and Freidinger, et al., J. Org. Chem., 47:104-109 (1982) where a dimethylsulfonium leaving group is generated from methyl iodide treatment of an alkyl methyl sulfide 17 to provide for lactam 18. A similar approach using a Mitsunobu reaction on an omega alcohol is found Holladay, et al., J. Org. Chem., 56:3900-3905 (1991).
In another method, lactams 20 can be prepared from cyclic ketones 19 using either the well known Beckmann rearrangement (e.g., Donaruma, et al., Organic Reactions, 11:1-156 (1960)) or the well known Schmidt reaction (Wolff, Organic Reactions, 3:307-336 (1946)) as shown in reaction (8) below: 
wherein L is as defined above.
Application of these two reactions leads to a wide variety of lactams especially lactams having two hydrogen atoms on the carbon alpha to the lactam carbonyl which lactams form a preferred group of lactams in the synthesis of the compounds of formula I above. In these reactions, the L group can be highly variable including, for example, alkylene, substituted alkylene and hetero containing alkylene with the proviso that a heteroatom is not adjacent to the carbonyl group of compound 19. Additionally, the Beckmann rearrangement can be applied to bicyclic ketones as described in Krow, et al., J. Org. Chem., 61:5574-5580 (1996).
The preparation of lactones can be similarly conducted using peracids in a Baeyer-Villiger reaction on ketones. Alternatively, thiolactones can be prepared by cyclization of an omega xe2x80x94SH group to a carboxylic acid and thiolactams can be prepared by conversion of the oxo group to the thiooxo group by P2S5 or by use of the commercially available Lawesson""s Reagent, Tetrahedron, 35:2433 (1979).
One recently reported route for lactam synthesis is a variation of the Schmidt reaction through the use of an alkyl azide, either intermolecularly or intramolecularly, through a tethered alkylazide function that attacks a ketone under acidic conditions. Gracias, et al., J. Am. Chem. Soc., 117:8047-8048 (1995) describes the intermolecular version whereas Milligan, et al., J. Am. Chem. Soc., 117:10449-10459 (1995) describes the intramolecular version. One example of the intramolecular version is illustrated in reaction (9) below: 
where R10 is exemplified by alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic.
In this reaction, ketone 21 is converted to an xcex1-(xcfx89-alkyl)ketone 22 which is cyclized to form bicyclic lactam 23. Such intramolecular reactions are useful in forming bicyclic lactams having 5-7 members and the lactam ring of 6-13 members. The use of hetero atoms at non-reactive sites in these rings is feasible in preparing heterobicyclic lactams.
Still another recent approach to the synthesis of lactams is described by Miller, et al., J. Am. Chem. Soc., 118:9606-9614 (1996) and references cited and is illustrated in reaction (10) below: 
where R6 and Pr are as defined above and R11 is exemplified by halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic wherein the aryl, heteroaryl, cycloalkyl and heterocyclic group is optionally fused to the lactam ring structure.
Specifically, in reaction (10), lactam 26 is formed from an appropriate unsaturated amide (e.g., 24) through a ruthenium or molybdenum complexes catalyzed olefin metathesis reaction to form unsaturated lactam 25 which can be used herein without further modification. However, the unsaturation in 25 permits a myriad of techniques such as hydroboration, Sharpless or Jacobsen epoxidations, Sharpless dihydroxylations, Diels-Alder additions, dipolar cycloaddition reactions and many more chemistries to provide for a wide range of substituents on the lactam ring. Moreover, subsequent transformations of the formed substitution leads to other additional substituents (e.g., mesylation of an alcohol followed by nucleophilic substitution reactions). See, for example, March, et al. Advanced Organic Chemistry, Reaction Mechanisms and Structure, 2nd Edition, McGraw-Hill Book Company, New York, N.Y., USA (1977) for a recitation of numerous such possible reactions. Saturated amides used in this reaction are conventional with amide 24 being commercially available.
Related chemistry to cyclize amides to form lactams is disclosed by Colombo, et al., Tetrahedron Lett., 35(23):4031-4034 (1994) and is illustrated in reaction (11) below: 
In this reaction, proline derivative 27 is cyclized via a tributyltin-radical cyclization to provide for lactam 28.
Some of the lactams described above contain the requisite amino group alpha to the lactam carbonyl whereas others did not. However, the introduction of the required amino group can be achieved by any of several routes delineated below which merely catalogue several recent literature references for this synthesis.
For example, in a first general synthetic procedure, azide or amine displacement of a leaving group alpha to the carbonyl group of the lactam leads to the alpha-aminolactams. Such general synthetic procedures are exemplified by the introduction of a halogen atom followed by displacement with phthalimide anion or azide and subsequent conversion to the amine typically by hydrogenation for the azide as described in Rogriguez, et al., Tetrahedron, 52:7727-7736 (1996), Parsons, et al., Biochem. Biophys. Res. Comm., 117:108-113 (1983) and Watthey, et al., J. Med. Chem., 28:1511-1516 (1985). One particular method involves iodination and azide displacement on, for example, benzyllactams as described by Armstrong, et al., Tetrahedron Lett., 35:3239 (1994) and by King, et al., J. Org. Chem., 58:3384 (1993).
Another example of this first general procedure for the synthesis of alpha-aminolactams from the corresponding lactam involves displacement of a triflate group by an azido group as described by Hu, et al., Tetrahedron Lett., 36(21):3659-3662 (1995).
Still another example of this first general procedure uses a Mitsunobu reaction of an alcohol and a nitrogen equivalent (either xe2x80x94NH2 or a phthalimido group) in the presence of an azodicarboxylate and a triarylphosphine as described in Wada, et al., Bull. Chem. Soc. Japan, 46:2833-2835 (1973) using an open chain reagent.
Yet another example of this first general procedure involves reaction of alpha-chlorolactams with anilines or alkyl amines in a neat mixture at 120xc2x0 C. to provide for 2-(N-aryl or N-alkyl)lactams as described by Gaetzi, Chem. Abs., 66:28690m.
In a second general synthetic procedure, reaction of an enolate with an alkyl nitrite ester to prepare the alpha oxime followed by reduction yields the alpha-aminolactam compound. This general synthetic procedure is exemplified by Wheeler, et al., Organic Syntheses, Coll. Vol. VI, p. 840 which describes the reaction of isoamyl nitrite with a ketone to prepare the desired oxime. The reduction of the oxime methyl ester (prepared from the oxime by reaction with methyl iodide) is described in the J. Med. Chem., 28(12):1886 (1985) and the reduction of alpha-oximino caprolactams by Raney-nickel and palladium catalysts is described by Brenner, et al., U.S. Pat. No. 2,938,029.
In a third general synthetic procedure, direct reaction of an enolate with an electrophilic nitrogen transfer agent can be used. The original reaction employed toluenesulfonyl azide but was improved as described by Evans, et al., J. Am. Chem. Soc., 112:4011-4030 (1990). Specifically, direct introduction of an azido group which can be reduced to the amine by hydrogenation is described by Micouin, et al., Tetrahedron, 52:7719-7726 (1996). Likewise, the use of triisopropylbenzenesulfonyl azide as the azide transferring agent for reaction with an enolate is described by Evans, et al., supra. The use of triphenylphosphine to reduce the alpha-azidolactams to the corresponding aminolactams in the benzodiazepine series is disclosed by Butcher, et al., Tetrahedron Lett., 37(37):6685-6688 (1996). Lastly, diazo transfer of beta-diketones and subsequent reduction of the diazo group to the amino group is exemplified by Hu, et al., Tetrahedron Lett., 36(21):3659-3662 (1995) who used Raney-nickel and hydrogen in acetic acid and acetic anhydride as the solvent.
In a fourth general procedure, N-substituted lactams are first converted to the 3-alkoxycarbonyl derivatives by reaction with a dialkyl carbonate and a base such as sodium hydride. See, for example, M. L. Reupple, et al., J. Am. Chem. Soc., 93:7021 et seq. (1971) The resulting esters serve as starting materials for conversion to the 3-amino derivatives. This conversion is achieved via the Curtius reaction as shown in reaction (12) below: 
where Pr is as defined above and R12 is typically hydrogen, an alkyl or an aryl group.
The Curtius reaction is described by P. A. S. Smith, Organic Reactions, 3:337-449 (1946). Depending on the reaction conditions chosen, Prxe2x95x90H or a protecting group such as Boc. For example, when Rxe2x95x90H, treatment of the acid with diphenylphosphoryl azide in the presence of t-butanol provides the product wherein Prxe2x95x90Boc.
The alpha-aminolactams employed as the cyclic amino compounds 2 in reaction (1) above include ring N-substituted lactams in addition to ring Nxe2x80x94H lactams. Some methods for preparing ring N-substituted lactams have been described above. More generally, however, the preparation of these compounds range from the direct introduction of the substituent after lactam formation to essentially introduction before lactam formation. The former methods typically employ a base and an primary alkyl halide although it is contemplated that a secondary alkyl halide can also be employed although yields may suffer.
Accordingly, a first general method for preparing N-substituted lactams is achieved via reaction of the lactam with base and alkyl halide (or acrylates in some cases). This reaction is quite well known and bases such as sodamide, sodium hydride, LDA, LiHMDS in appropriate solvents such as THF, DMF, etc. are employed provided that the selected base is compatible with the solvent. See for example: K. Onito, et al., Tetrahedron, 36:1017-1021 (1980) and J. E. Semple, et al., J. Med. Chem., 39:4531-4536 (1996) (use of LiHMDS with either Rxe2x80x94X or acrylates as electrophiles).
A second general method employs reductive amination on an amino function which is then cyclized to an appropriate ester or other carbonyl function.
A third general method achieves production of the N-substitution during lactam formation. Literature citations report such production from either photolytic or thermal rearrangement of oxaziridines, particularly of N-aryl compounds. See, for example, Krimm, Chem. Ber., 91:1057 (1958) and Suda, et al., J. Chem. Soc. Chem Comm., 949-950, (1994). Also, the use of methyl hydroxylamine for the formation of nitrones and their rearrangement to the N-methyl derivatives is reported by Barton, et al., J. Chem. Soc., 1764-1767 (1975). Additionally, the use of the oxaziridine process in chiral synthesis has been reported by Kitagawa, et al., J. Am. Chem. Soc., 117:5169-5178 (1975).
A more direct route to obtain N-phenyl substituted lactams from the corresponding NH lactams through the use of t-butyltetramethylguanidine and triphenylbismuth dichloride is disclosed by Akhatar, et al., J. Org. Chem., 55:5222-5225 (1990) as shown in reaction (13) below. 
Given that numerous methods are available to introduce an alpha-amino group onto a lactam (or lactone) ring, the following lactams (and appropriate corresponding lactones) are contemplated for use in the synthesis of compounds of formula I above. Similar alcohol functions at the carbonyl position are derivative of either amine ring opening of cyclic epoxides, ring opening of aziridines, displacement of appropriate halides with amine or alcohol nucleophiles, or most likely reduction of appropriate ketones. These ketones are also of interest to the present invention.
Monocyclic lactams as described by Nedenskov, et al., Acta Chem. Scand., 12:1405-1410 (1958) and represented by the formula: 
where R1 and R2 are exemplified by alkyl, aryl or alkenyl (e.g., allyl).
Monocyclic lactams containing a second nitrogen ring atom as described by Sakakida, et al., Bull. Chem. Soc. Japan, 44:478480 (1971) and represented by the formula: 
where R is exemplified by CH3xe2x80x94 or PhCH2xe2x80x94.
Monocyclic lactams having hydroxyl substitution on the ring as described by Hu, et al., Tetrahedron Lett., 36(21):3659-3662 (1995) and represented by the formula: 
where R is exemplified by benzyl (includes both the cis and trans hydroxy lactams).
The direct preparation N-substituted lactams of 5-8 members from the corresponding ketones is described by Hoffman, et al., Tet. Lett., 30:4207-4210 (1989). These lactams are represented by the formula: 
wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, or benzyl.
N-methoxylactams prepared from cyclohexanone and dimethoxyamine are described by Vedejs, et al., Tet. Lett., 33:3261-3264 (1992). These structures are represented by the formula: 
Substituted 3-aminoazetidinone derivatives prepared by a variety of routes including those described by van der Steen, et al., Tetrahedron, 47, 7503-7524 (1991)56, Hart, et al., Chem Rev., 89:1447-1465 (1989) and references cited therein are represented by the formula: 
where R1 and R2 are independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic or are fused to form a cyclic group.
Ring substituted lactams are described by Lowe, et al., Bioorg. Med. Chem. Lett., 4:2877-2882 (1994) and are represented by the formula: 
wherein R2 and R3 are exemplified by aryl and substituted aryl and R1 is exemplified by alkyl or hydrogen.
The synthesis of substituted 3-aminopyrrolidones from alpha-bromoketones is described by McKennis, Jr., et al., J. Org. Chem., 28:383-387 (1963). These compounds are represented by the formula: 
where R1 is aryl or heteroaryl and R2 corresponds to any substituent for which the corresponding amine R2xe2x80x94NH2 exists.
Additional references for the synthesis of alpha aminolactams are as follows:
1. Shirota, et al., J. Med. Chem., 20:1623-1627 (1977) which describes the synthesis of a compound of the formula: 
2. Overberger, et al., J. Am. Chem. Soc., 85:3431 (1963) which describes the preparation of optically active xcex2-methylcaprolactam of the formula: 
3. Herschmann, Helv. Chim. Acta, 32:2537 (1949) describes the synthesis of a disubstituted caprolactam from the Beckmann rearrangement of menthone which is represented by the formula: 
4. Overberger, et al., Macromolecules, 1:1 (1968) describes the synthesis of eight-membered lactams from 3-methylcycloheptanone as shown below: 
5. The synthesis of benzolactams (benzazepinones) has been reported by Busacca, et al., Tet. Lett., 33:165-168 (1992): 
xe2x80x83by Croisier, et al., U.S. Pat. No. 4,080,449: 
xe2x80x83and by J. A. Robl, et al., Tetrahedron Lett., 36(10):1593-1596 (1995) who employed an internal Friedel-Crafts like cyclization to prepare the tricyclic benzyllactams shown below where Pht is the phthalimido protecting group: 
Another tricyclic lactam series is disclosed by Flynn, et al., J. Med. Chem., 36:2420-2423 (1993) and references cited therein.
6. Orito, et al., Tetrahedron, 36:1017-1021 (1980) discloses phenyl substituted benzazepinones represented by the formula: 
xe2x80x83wherein Rxe2x95x90H or CH3xe2x80x94;
Kawase, et al., J. Org. Chem., 54:3394-3403 (1989) discloses a N-methoxy benzazepinone represented by the formula: 
7. Lowe, et al., J. Med. Chem., 37:3789-3811 (1994) describes several synthetic pathways to substituted benzazepinones of the formula: 
xe2x80x83where R1 is substituted aryl or cyclohexyl, X is a suitable substituent and R2 can be H or alkyl. The syntheses described in Lowe are, however, adaptable to form numerous R1 substituents.
8. Robl, et al., Bioorg. Med. Chem. Lett., 4:1789-1794 (1994) and references cited therein as well as Skiles, et al., Bioorg. Med. Chem. Lett., 3:773-778 (1993) disclose benzofused lactams which contain additional heteroatoms in the lactam ring. These compounds are represented by the formula: 
xe2x80x83where X is O and R2xe2x95x90H or CH3 or Xxe2x95x90S and R2xe2x95x90H. In either case, R1xe2x95x90H or alkyl. Also, in Skiles, the thio group of the thiolactam can be oxided to the SO2 group. These structures are also presented from Beckmann rearrangement in Grunewald, et al., J. Med. Chem., 39(18):3539 (1996).
9. Also syntheses for the benzoheterolactam series is presented in Thomas, et al., J. Chem. Soc., Perkin II, 747 (1986) which could lead to compounds of the formula: 
xe2x80x83where X is O or H2 and R is CO2R.
10. Further examples of benzazepinones are found in Warshawsky, et al., Bioorg. Med. Chem. Lett., 6:957-962 (1996) which discloses compounds of the formula: 
xe2x80x83The synthesis can be generalized to produce Rxe2x95x90alkyl or aryl.
11. Ben-Ishai, et al., Tetrahedron, 43:439-450 (1987) describes syntheses which could lead to several benzolactams of the formula: 
xe2x80x83wherein n 0, 1, or 2 and Rxe2x95x90xe2x80x94CH3, PhCH2xe2x80x94 and H.
12. van Niel et al., Bioorg. Med. Chem. Lett., 5:1421-1426 (1995) reports the synthesis of compounds of the formulas: 
xe2x80x83wherein X is xe2x80x94OH, xe2x80x94NH2 or xe2x80x94NR6R6 where R6 is as defined above. The reported ketone is a versatile synthetic intermediate which can be modified by conventional methods such as reductive amination, reduction, etc.
13. Kawase, et al., J. Org. Chem., 54:3394-3403 (1989) describes a synthetic method for the preparation of: 
In addition to the above, saturated bicyclic alpha-aminolactams are also contemplated for use in the synthesis of compounds of formula I. Such saturated bicyclic alpha-aminolactams are well known in the art. For example, Edwards, et al., Can. J. Chem., 49:1648-1658 (1971) describes several syntheses of bicyclic lactams of the formula: 
Similarly, Milligan, et al., J. Am. Chem. Soc., 117:10449-10459 (1995) and references cited therein report the synthesis of lactams of the formula: 
wherein R1 and R2 are H or xe2x80x94CH3, ring A can have from 6-13 members and ring B can have from 5-7 members. R can be alkyl, aryl, cycloalkyl and the like.
The introduction of a heteroatom into the saturated cyclic structure fused to the lactam ring is disclosed by Curran et al., Tet. Lett., 36:191-194 (1995), who describe a synthetic method which can be used to obtain a lactam of the formula: 
by Slusarchyk, et al., Bioorg. Med. Chem. Lett., 5:753-758 (1995), who describe syntheses which could lead to a lactam of the formula: 
and by Wyvratt, et al., Eur. Pat. Appl. 61187 (1982), who describe a lactam of the formula: 
Lactams having further heteroatom(s) in the cyclic lactam structure (in addition to the nitrogen of the amido group of the lactam) are described by Cornille, et al., J. Am. Chem. Soc., 117:909-917 (1995), who describe lactams of the formula: 
and J. Kolc, Coll. Czech. Chem. Comm., 34:630 (1969), who describes lysines suitable for cyclization to lactams which have a hetero lactam ring atom as shown by the formula: 
where Xxe2x95x90O, S and NR where R is, for example, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic, and the like.
Similarly, each of Dickerman, et al., J. Org. Chem., 14:530 (1949)86, Dickerman, et al., J. Org. Chem., 20:206 (1955), and Dickerman, et al., J. Org. Chem., 19:1855 (1954) used the Schmidt and Beckmann reactions on substituted 4-piperidones to provide for lactams of the formula: 
where R is acyl, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic provided that R is not an acid labile group such as t-Boc; and Rxe2x80x2 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclicoxy, halo, cyano, nitro, trihalomethyl, and the like.
An internal cyclization of appropriate ethylenediamine amides onto a ketone or aldehyde is described by Hoffman, et al., J. Org. Chem., 27:3565 (1962) as follows: 
Ring expansion methodology based on beta lactams to provide for larger ring lactams containing an aza group has twice been reported in Wasserman, et al., J. Am. Chem. Soc., 103:461-2 (1981) and in Crombie, et al., Tetrahedron Lett., 27(42):5151-5154 (1986).
Dieckmann methodology has been used to prepare aza caprolactams from unsymmetrical amines such as shown below by Yokoo, et al., Bull, Chem. Soc. Jap., 29:631 (1956). 
where R is as defined in this reference. The disclosure of Yokoo, et al. can be extended to cover R being alkyl, substituted alkyl, aryl, alkoxy, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic, alkenyl, substituted alkenyl, and the like.
The synthesis of various members of the oxalactam series has been reported by Burkholder, et al., Bioorg. Med. Chem. Lett., 2:231 (1993) and references cited therein which oxalactams are represented by the formula: 
where xe2x80x2R is as defined in the reference and R can be alkyl, substituted alkyl, aryl, alkoxy, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic, alkenyl, substituted alkenyl, and the like.
The synthesis of thialactams (generally oxalactams can be made by the same methodology) has been reported by Freidinger, et al., J. Org. Chem., 47:104-109 (1982), who prepared thialactams of the formula: 
This reference provides a series of procedures having broad application for synthesis of lactams permitting R in the above formula to be derived from any amine (alkyl, aryl, heteroaryl, etc.) with the restriction being that the R-group does not contain any functional groups reactive with formaldehyde (e.g., primary and secondary amines). The general synthetic scheme provided by Freidlinger, et al. is: 
The coupling agent is any standard reagent used in the formation of typical peptide or amide bonds, for example, carbodiimide reagents. See, also, Karanewsky, U.S. Pat. No. 4,460,579 and Kametani, et al., Heterocycles, 9:831-840 (1978).
The Friedinger procedure can be extended to afford disubstituted thialactams of the following structure: 
In this procedure, the thiolactam ring is prepared as follows: 
In practical terms, R2 will be limited to aryl and heteroaryl groups and sterically hindered alkyl groups such as t-butyl. R1 can be highly variable and is limited only by subsequent reaction steps.
Still further is the Kametani procedure which provides for lactams as follows: 
In principle, the Kametani procedure allows for a wide selection of R1 and R2 groups limited primarily by stability to the reaction conditions.
See, for example, Yanganasawa, et al., J. Med. Chem., 30:1984-1991 (1987) and J. Das et al., Biorg. Med. Chem. Lett., 4:2193-2198 (1994) which describes general methods for the synthesis of isomeric 7-membered thialactams of the following structure: 
The first synthetic route is: 
R2 can be highly variable (e.g., alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic and the like) since a number of well documented routes exist for the synthesis of nitroethylene derivatives from aldehydes and nitromethane (Henry reaction) followed by dehydration. R1 is limited to groups that can undergo alkylation reactions. 
In this procedure, R2 can be highly variable. The starting component required to introduce R2 can be readily derived by the reduction of any known alpha-BOC-amino acid to the alcohol derivative followed by formation of the mesylate.
As noted above, the primary approaches to the preparation of lactams is the Beckmann/Schmidt ring expansion reaction using either inter- or intramolecular approaches serves to prepare lactams of various ring sizes. The intramolecular approach generates bicyclic materials with the lactam nitrogen incorporated into the ring fusion. Additional approaches set forth above are at the base of the methodology are internal cyclization of omega-amino acids/esters where the construction of the substituent pattern takes place prior to cyclization, and internal cyclization of an electrophilic center onto a nucleophilic functional group as in the Friedel Crafts type cyclization at the center of the Ben-Ishal procedure for making benzazepinones. This latter procedure is applicable to a wide variety of heteroaromatics as well as benzenoid rings, and may also be applied to non-aromatic double or triple bonds to generate a wide array of substituents or ring fusions.
Deoxygenation of the lactam by reagents such as diborane, LiAlH4, and the like leads to azaheterocycles (xe2x95x90X is dihydro).
Similarly, for Uxe2x95x90H, OH, such compounds can be prepared by epoxidation of cycloalkenyl groups followed by oxirane opening by, e.g., ammonia. After formation of compounds of formula I, xe2x95x90U being H, OH can be oxidized to provide for cycloalkylones (xe2x95x90X being oxo).
Additionally, the 5,7-dihydro-6H-diben[b,d]azepin-6-one derivatives employed in this invention can be prepared using conventional procedures and reagents. For example, an appropriately substituted N-tert-Boc-2-amino-2xe2x80x2-methylbiphenyl compound can be cyclized to form the corresponding 5,7-dihydro-6H-diben[b,d]azepin-6-one derivative by first treating the biphenyl compound with about 2.1 to about 2.5 equivalents of a strong base, such as sec-butyl lithium. This reaction is typically conducted at a temperature ranging from about xe2x88x9280xc2x0 C. to about xe2x88x9260xc2x0 C. in an inert diluent such as THF. The resulting dianion is then treated with dry carbon dioxide at a temperature of about xe2x88x9278xc2x0 C. to afford the 5,7-dihydro-6H-diben[b,d]azepin-6-one. This procedure is described further in R. D. Clark et al., Tetrahedron, 49(7), 1351-1356 (1993) and references cited therein.
After forming the 5,7-dihydro-6H-diben[b,d]azepin-6-one, the amide nitrogen can be readily alkylated by first treating the dibenazepinone with about 1.1 to about 1.5 equivalents of a strong base, such as sodium hydride, in an inert diluent, such as DMF. This reaction is typically conducted at a temperature ranging from about xe2x88x9210xc2x0 C. to about 80xc2x0 C. for about 0.5 to about 6 hours. The resulting anion is then contacted with an excess, preferably about 1.1 to about 3.0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide. Generally, this reaction is conducted at a temperature of about 0xc2x0 C. to about 100xc2x0 C. for about 1 to about 48 hours.
An amino group can then be introduced at the 5-position of the 7-alkyl-5,7-dihydro-6H-diben[b,d]azepin-6-one using conventional procedures and reagents. For example, treatment of 7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one with an excess of butyl nitrite in the presence of a strong base, such as potassium 1,1,1,3,3,3-hexamethyldisilazane (KHMDS), affords 5-oximo-7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one. Subsequent reduction of the oximo group by hydrogenation in the presence of a catalyst, such as palladium on carbon, then provides 5-amino-7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one. Other conventional amination procedures, such as azide transfer followed by reduction of the azido group, may also be employed.
Similarly, various benzodiazepine derivatives suitable for use in this invention can be prepared using conventional procedures and reagents. For example, a 2-aminobenzophenone can be readily coupled to xcex1-(isopropylthio)-N-(benzyloxycarbonyl)glycine by first forming the acid chloride of the glycine derivative with oxayl chloride, and then coupling the acid chloride with the 2-aminobenzophenone in the presence of a base, such as 4-methylmorpholine, to afford the 2-[xcex1-(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]-aminobenzophenone. Treatment of this compound with ammonia gas in the presence of an excess, preferably about 1.1 to about 1.5 equivalents, of mercury (II) chloride then affords the 2-[N-(xcex1-amino)-Nxe2x80x2-(benzyloxycarbonyl)-glycinyl]aminobenzophenone. This intermediate can then be readily cyclized by treatment with glacial acetic acid and ammonium acetate to provide the 3-(benzyloxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one1. Subsequent removal of the Cbz group affords the 3-amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one.
Alternatively, 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-ones can be readily aminated at the 3-position using conventional azide transfer reactions followed by reduction of the resulting azido group to form the corresponding amino group. The conditions for these and related reactions are described in the examples set forth below. Additionally, 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-ones are readily alkylated at the 1-position using conventional procedures and reagents. For example, this reaction is typically conducted by first treating the benzodiazepinone with about 1.1 to about 1.5 equivalents of a base, such as sodium hydride, potassium tert-butoxide, potassium 1,1,1,3,3,3-hexamethyldisilazane, cesium carbonate, in an inert diluent, such as DMF. This reaction is typically conducted at a temperature ranging from about xe2x88x9278xc2x0 C. to about 80xc2x0 C. for about 0.5 to about 6 hours. The resulting anion is then contacted with an excess, preferably about 1.1 to about 3.0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide. Generally, this reaction is conducted at a temperature of about 0xc2x0 C. to about 100xc2x0 C. for about 1 to about 48 hours.
Additionally, the 3-amino-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines employed in this invention are typically prepared by first coupling malonic acid with a 1,2-phenylenediamine. Conditions for this reaction are well known in the art and are described, for example, in PCT Application WO 96-US8400 960603. Subsequent alkylation and amination using conventional procedures and reagents affords various 3-amino-1,5-bis(alkyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines. Such procedures are described in further detail in the example set forth below.
Accordingly, a vast number of lactams, lactones and thiolactones are available by art recognized procedures. Similarly, the art is replete with examples of aminocycloalkyl compounds for use in the synthesis of compounds of formula I above.
In the synthesis of compounds of formula I using the synthetic methods described above, the starting materials can contain a chiral center (e.g., alanine) and, when a racemic starting material is employed, the resulting product is a mixture of R,S enantiomers. Alternatively, a chiral isomer of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained. Such reaction protocols can involve inversion of the chiral center during synthesis.
Accordingly, unless otherwise indicated, the products of this invention are a mixture of diastereomers or R,S enantiomers. Preferably, however, when a chiral product is desired, the chiral product corresponds to the L-amino acid derivative. Alternatively, chiral products can be obtained via purification techniques which separates diastereomers or enantiomers to provide for one or the other stereoisomer. Such techniques are well known in the art.
Pharmaceutical Formulations
When employed as pharmaceuticals, the compounds of formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I above associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term xe2x80x9cunit dosage formsxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Preferably, the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient""s symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.